FDA rebukes Advocate Health Care

FDA

FDA warning letter start from website

FDA warning letter start from website

Deborah L. Shelton, Chicago Tribune reporter

The U.S. Food and Drug Administration has sharply criticized Advocate Health Care, the state's largest health system, for enrolling emergency room patients in a clinical trial without their permission.

In a warning letter made public this week, the FDA questioned a study designed to evaluate the effectiveness of a sedative called etomidate. The subjects were patients at Advocate Christ Medical Center in Oak Lawn who needed intubation, an emergency procedure in which a tube is inserted down the throat to open the airway or deliver medication.

The study proposal originally stated that the patients being intubated would receive whatever drug the doctor preferred and clinical outcome data would be collected from their records after the fact.

Advocate Health Care's institutional review board reviewed the project in December 2006 and determined that patient consent was not needed because it involved reviewing the files of people who already had been treated. Institutional review boards, or IRBs, are responsible for overseeing research involving human subjects to make sure their rights are protected.

But in July 2007, the clinical investigator proposed that the subjects of the study should be randomly selected to receive either etomidate or midazolam, another drug. Both medications are FDA-approved, but researchers had hypothesized that patients given etomidate would fare worse. All patients in the study had sepsis, a life-threatening blood infection, at the time of treatment.

The IRB approved the modification in September 2007 and allowed the clinical investigation to continue without lifting the informed consent waiver.

But according to the FDA, the alterations to the study made it a clinical investigation subject to federal regulations. Among other requirements, Advocate's IRB was required to make sure that each subject or that person's legally authorized representative gave consent.

"The IRB did not 'make a connection' that FDA regulations applied," said the warning letter, which mentioned that an FDA inspector uncovered the "objectionable conditions" during a routine inspection last November.

"The IRB's failure to meet this responsibility is particularly concerning because the concept of informed consent is fundamental to the conduct of ethical research," it said.

The study involved 122 patients and ended in December 2010, according to the National Institutes of Health. The FDA's warning letter to Advocate Health Care's review board, dated June 1, was posted on the FDA's website this week.

A spokeswoman for Oak Brook-based Advocate Health Care did not make an official available for questions, saying Friday that the health system was still working on its response to the FDA.

"We take this matter very seriously," Advocate said in a statement. "Our goal is to make sure that all of our Institutional Review Board activities, protocols and procedures related to clinical studies are in full compliance with FDA regulations. We have taken immediate steps to ensure this does not occur again and we are fully confident the matter will be resolved with the FDA shortly."

Dr. Michael Carome, former associate director for regulatory affairs with the U.S. Department of Health and Human Services' Office for Human Research Protections, said the study changed in a fundamental way when patients were randomly assigned to receive one of the two drugs.

Instead of a doctor making a clinical decision about which medication to use, he said, the drug was selected according to the study protocol.

"The importance of getting informed consent is even more heightened in that situation," said Carome, now deputy director of Public Citizen's Health Research Group, a consumer advocacy organization.

The FDA's letter ordered the health system to notify the FDA in writing of the actions it planned to take to prevent similar violations in the future. The warning letter said failure to explain the violations "adequately and promptly may result in regulatory action without further notice."

Officials at Advocate Health Care already had sent the FDA a corrective action plan, but the agency found it unacceptable. The letter stated that Advocate's IRB did not review a letter that the clinical investigator mailed to subjects after the study was completed to make sure it provided appropriate information.

"In addition, we find the clinical investigator's letter to the subjects to be deficient because, among other things, it did not (1) inform the subject unambiguously that he/she was enrolled in a research study, or (2) include details of the study and other information that should have been contained in the informed consent document, including information about risk to the subject," the FDA letter said.

Carome said allowing the study to go forward without obtaining patients' consent was mind-boggling.

"It is a fundamental failure of the IRB," Carome said, "and it is really astonishing in 2012, when you consider that human subject protections have been at the forefront of research for the last three to four decades."